The goal of this Program Project Grant is to elucidate the role of the phosphoinositide 3-kinase (PI3K) pathway in prostate cancer and to identify new targets for pharmaceutical intervention in this disease. At that time that this program was conceived 5 years ago, evidence was emerging, based on loss of PTEN, that the PI3K pathway was involved in human prostate cancer. Our progress in elucidating the PI3K pathway and in generating mouse models that mimic human disease has led to the identification of essential components of PI3K signaling in prostate cancer and suggested new treatments and biomarkers. The experiments proposed in the next granting period are a logical extension of this work and take us in some new directions. Most notably, we have combined Project 1 (Cantley) and Project 2 (Roberts) from the previous funding period into a single project (Project 1 of this proposal) and have added a new investigator, Dr. Charles Sawyers, as leader of a new project (Project 3). Each of the three Projects focuses on developing mouse models that can be analyzed in a parallel fashion to determine the importance of distinct components of the PI3K signaling pathway in prostate cancer. Project 1 (Cantley and Roberts) addresses the importance of individual catalytic and regulatory subunits of PI3K in prostate tumors that result from loss of PTEN and addresses the ability of a mutant form of p110a (found in human prostate tumors by Dr. Sellers) to induce prostate neoplasia in mice. Project 2 (Sellers) focuses on using gene expression profiles to determine pathways that mediate prostate intraepithelial neoplasia (PIN) in mice expressing activated AKT in the prostate and in comparing these profiles to those observed in other mouse models derived in Projects 2 and 3 and to expression profiles in human tumors. Project 3 (Sawyers) addresses pathways downstream of PI3K, independent of AKT signaling, that contribute to prostate cancer. Dr. Sawyers has observed that the Jnk Ser/Thr kinase is activated in cells lacking PTEN and that deletion of Jnk impairs proliferation of these cells. Dr. Sawyers will generate mouse models to test the importance of Jnk for prostate tumor formation due to loss of PTEN. A Mouse Transgenic Core (DePinho) will generate the mice needed for the three projects and a Pathology Core (Loda) and Genomics and Bioinformatics Core (Golub) will analyze and compare the tumors generated in the three Projects. An Administrative Core (Cantley) will supervise all aspects of the program.